US3934013A - Pharmaceutical composition - Google Patents

Pharmaceutical composition Download PDF

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Publication number
US3934013A
US3934013A US05/551,811 US55181175A US3934013A US 3934013 A US3934013 A US 3934013A US 55181175 A US55181175 A US 55181175A US 3934013 A US3934013 A US 3934013A
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Prior art keywords
weight
compound
composition
corticosteroids
solvent
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US05/551,811
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English (en)
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Boyd J. Poulsen
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Syntex USA LLC
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Syntex USA LLC
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Priority to US05/551,811 priority Critical patent/US3934013A/en
Application filed by Syntex USA LLC filed Critical Syntex USA LLC
Priority to IL48797A priority patent/IL48797A/xx
Priority to ZA760071A priority patent/ZA7671B/xx
Publication of US3934013A publication Critical patent/US3934013A/en
Application granted granted Critical
Priority to CA244,385A priority patent/CA1067409A/en
Priority to GB3426/76A priority patent/GB1502544A/en
Priority to AU10682/76A priority patent/AU504748B2/en
Priority to AU10858/76A priority patent/AU481367B2/en
Priority to BR7600834A priority patent/BR7600834A/pt
Priority to DE19762605242 priority patent/DE2605242A1/de
Priority to FI760344A priority patent/FI67415C/fi
Priority to ES445151A priority patent/ES445151A1/es
Priority to NZ180042A priority patent/NZ180042A/xx
Priority to IT67379/76A priority patent/IT1066085B/it
Priority to FR7604592A priority patent/FR2301262A1/fr
Priority to NL7601667A priority patent/NL7601667A/xx
Priority to BE164436A priority patent/BE838711A/xx
Priority to IE331/76A priority patent/IE43655B1/en
Priority to DK68876*#A priority patent/DK68876A/da
Priority to JP51017820A priority patent/JPS6135166B2/ja
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to topical anti-inflammatory pharmaceutical compositions which are useful for treating diseases of the skin, particularly inflammatory manifestations of corticosteroid-responsive dermatoses.
  • the composition comprises a suitable pharmaceutical solvent and dissolved therein at least two corticosteroid compounds defined hereinafter, each corticosteroid being present at a specific amount relative to the others.
  • the new compositions of this invention provide improvement in the treatment of inflamed condition of the skin.
  • a new method for the preparation of the compositions of this invention is also disclosed.
  • the primary barrier to the precutaneous absorption of drugs has been identified as the stratum corneum, the layer of stratified and keratinized dead cells at the skin surface.
  • the ability of chemical agents or drugs to diffuse across the stratum corneum into the deeper tissues is directly related to the physical chemical properties of the drugs. It is known that certain low molecular weight organic solvents such as acetone, chloroform, and dimethyl sulfoxide penetrate the human skin more readily (i.e. at a faster rate) than most drugs, particularly substances of high molecular weight such as corticosteroids. For such compounds, the therapeutic effectiveness is greatly dependent on the rate of diffusion from the topical vehicle (the base) into the skin, i.e. the penetration rate. Increasing the rate of diffusion is an important mechanism for improving therapeutic effectiveness of many topically applied drugs.
  • Marcus et al. [J. Pharm. Sci., 54, 495-6 (1965)] have described improved in vitro release into water for mixtures of two steroids. In their report data are present for two different mixtures: dexamethasone plus prednisolone and dexamethasone plus betamethasone.
  • the systems described by Marcus et al. differ completely from those described in the present invention.
  • an experimental situation is described where release from the vehicle is the rate-limiting step in diffusion instead of diffusion through the skin barrier -- the case which normally prevails in the precutaneous absorption of drugs.
  • Marcus et al. describe formulations where the drug is present primarily as suspended solid particles instead of the solubilized systems described in this invention.
  • pregnenolone hemiesters and their salts may be applied topically as a mixture for the treatment of alleviating allergic, pruritic and inflammatory skin conditions. See for example U.S. Pat. No. 3,197,367 issued July 27, 1965 to Panzarella. Not only is this class of compounds completely different from the corticosteroids employed in the composition of this invention, but also a greater percentage of the active ingredients is required for therapeutic activity. It is also mentioned in U.S. Pat. No. 3,743,741 issued July 3, 1973 to Laurent et al. that mixtures of two 9-chloro substituted prednisolones may be used as an ointment. No particular advantage of the mixture over either one alone at an equivalent concentration is discussed, however.
  • the combination composition of this invention can be adjusted so that the total concentration of the individual drugs used is small enough to reduce the potential for side effects of any of the individual drugs used at a concentration equivalent to the total concentration of each corticosteroid used in the composition of this invention. This results, of course, in a safer drug composition.
  • this invention is a topical, antiinflammatory, pharmaceutical composition which comprises
  • corticosteroids at least two corticosteroids, each dissolved in the solvent at a concentration equal to the saturation solubility for each corticosteroid, the corticosteroids being chosen from the group represented by the following formulas: ##SPC1##
  • R is ##EQU1## in compound (B) R is H, in compound (C) R is ##EQU2## in compound (D) R is ##EQU3## in compound (E) R is ##EQU4## in compound (F) R is ##EQU5## ##SPC2## in compound (G) R 1 is F; X and X 1 both Cl, Z is a double bond,
  • R 1 is OH; X and X 1 are both Cl, Z is a double bond,
  • R 1 is OH; X is H and X 1 is OH, Z is a single bond,
  • the solvent in the composition of this invention is a mixture of about 15% by weight or more of a glycol, preferably propylene glycol, and about 85% by weight or less water.
  • the corticosteroid mixture comprises 3 compounds chosen from the group A,C,D,E, and F, more specifically compounds A,C and D.
  • Other preferred aspects of the composition of this invention will be discussed hereinafter.
  • Another aspect of this invention is a process of treating inflammatory conditions which process comprises topically administering an effective amount of the composition of this invention.
  • Still another aspect of this invention is a process for preparing the composition of this invention which process comprises
  • a topical, anti-inflammatory, pharmaceutical composition which comprises about 0.001%w to about 0.5%w of said corticosteroids.
  • the essence of the invention is utilizing a mixture of active ingredients, steroids, hereinafter defined, each of which has a chemical structure differing from the others but each having similar therapeutic (anti-inflammatory) activities, the steroids being present in solution at specific ratios relative to each other, the ratios being governed at least in part by the concentration of each steroid, which is equal to its saturation solubility in the solvents employed.
  • the mixture is dissolved in a suitable pharmaceutical solvent which may be substantially anhydrous or may be mixed with water, depending on what type of formulation will be used for topical application, i.e. cream, ointment, lotion, gel, or the like.
  • the steroids are more soluble in anhydrous solvents such as a glycol than in a solvent/water mixture and the exact ratio of steroids will be affected by the presence of water, each steroid having its own independent solubility characteristics in each solvent system being employed.
  • the ratios given for compounds found to be useful in this invention [(A) through (K), below] are set by arbitrarily giving compound (A) the value of 1.00 and relating the relative amounts of the other steroids present to compound (A). Each has then a ratio range relative to A and to each other steroid.
  • the specific multisteroid composition of this invention offers certain advantages over comparable single steroid compositions known in the art.
  • (1) The activity, as measured by the rate of total steroid penetration across the stratum corneum is greater for the composition of this invention than for a single steroid composition of equivalent concentration.
  • (3) Reduced doses of the individual steroids may be used due to superior total penetration.
  • the potential for side effects in the target species is reduced because of the lower total dose of drug required.
  • topical, anti-inflammatory compositions having low glycol solvent contents to reduce the chance of irritation in users who have an adverse reaction to glycols, such as propylene glycol.
  • topical, anti-inflammatory, pharmaceutical composition of this invention comprises
  • corticosteroids are chosen from the group represented by the formulas (A) through (K) presented hereinafter, the total concentration of corticosteroids dissolved being less than about 0.5% by weight of the final pharmaceutical composition and the corticosteroids being present in amounts relative to each other such that the activity, as measured by the total steroid penetration rate across a membrane, such as the stratum corneum, is greater for the mixture than for any of the corticosteroids alone at an equivalent total amount.
  • a pharmaceutically acceptable solvent is one which (i) is substantially non-toxic and non-irritating under the conditions used, (ii) will dissolve a sufficient amount of the drugs used to give the desired effect, and (iii) may be readily formulated into any of the classical drug formulations such as creams, ointments, lotions, or gels.
  • Particularly suitable solvents include water, glycerin, propylene carbonate, and glycols such as a 1,2-propylene diol (i.e. propylene glycol), 1,3-propylene diol or mixtures thereof; polyethylene glycol having molecular weight of from 100 to 800; dipropylene glycol; etc.; and mixtures of the aforementioned with each other.
  • the pharmaceutically acceptable solvent will be a glycol, particularly propylene glycol (PG), either alone or admixed with water.
  • PG propylene glycol
  • a particularly preferred solvent comprises 15% by weight or more of a suitable glycol, preferably PG, and 85% by weight or less water.
  • the topical, anti-inflammatory pharmaceutical composition of this invention requires that at least two of the corticosteroid, compounds, and preferably no more than 5, be present in solution, the compounds being chosen from those represented by the following structures (A) through (K) in relative amounts shown adjacent the respective structures; each of the drugs being present at concentration in the pharmaceutically acceptable solvent equal to that drug's saturation solubility in the solvent.
  • the solvent comprises at least 15% by weight (%w) propylene glycol or more and 85% w water or less.
  • the compounds are represented by: ##SPC4##
  • R is ##EQU7## present at 1.00 relative part;
  • R is --H present at 22-33 relative parts;
  • (G) Z is a double bond, R 1 is F and X and X 1 and Cl: present at 0.02-0.25 relative part;
  • Compounds A through F, I and J may be prepared by methods known in the art, particularly those disclosed in U.S. Pat. No. 3,126,375 to Ringold, et al. and U.S. Pat. No. 3,014,938 to Mills et al.
  • Compound G may be prepared as disclosed in U.S. Pat. No. 3,409,613 to Fried; compound H by the methods disclosed in U.S. Pat. No. 3,201,391 to Bowers; and compound K by methods shown in J. Am. Chem. Soc. 81, 3156 (1959). As much of these patents or journals as is pertinent is incorporated herein by reference.
  • the mixtures of this composition include those compounds from those represented by A through K which have about the same level of solubility.
  • a formulation which is substantially anhydrous meaning less than about 3%w water
  • a pharmaceutically acceptable solvent such as propylene glycol
  • the solvent is a mixture of about 60%w PG and 40%w water
  • the following mixtures and ratios are exemplary, but again are not to be construed as limiting:
  • the enhanced penetration effects of these combinations may be seen over a wide range of concentrations as long as the drugs are kept at their saturation solubility.
  • the mixture of corticosteroids is dissolved at levels which depend on the particular solvent and may vary from about 1.0 microgram (mg)/milliliter (ml) of solvent to about 10 milligrams (mg)/milliliter of solvent to obtain the increased penetration rate.
  • the mixture of corticosteroids is first dissolved in the solvent then formulated into a composition which may be applied topically as any suitable classical formulation as described in the United States Pharmacopoeia XVII, for example as a (1) cream, (2) ointment, (3) lotion, or (4) gel, the total corticosteroid concentration in the final formulation being a therapeutically effective amount which will generally be between about 0.001 and 0.5%w, preferably less than about 0.2%w but more than about 0.005%w.
  • the corticosteroids are dissolved in the solvent and are at their saturation solubility concentrations, i.e, the maximum amount dissolved in the solvent at a given temperature.
  • the presence of excess steroid in the pure form does not significantly enhance the rate of penetration of the composition.
  • the majority of each of the drugs present is in solution.
  • the group of corticosteroids which are eminently suitable for use in the composition of this invention are those which exhibit about the same level of solubility in the solvent employed.
  • Such a group comprises a mixture of at least 2 of the compounds represented by the formulas A, C--H, J, and K.
  • corticosteroids chosen from the fluocinolone acetonide esters represented by formulas A,C,D,E and F above.
  • this invention is a topical, anti-inflammatory, pharmaceutical composition which comprises
  • a suitable pharmaceutical solvent preferably about 1 to 99.9%w of a mixture of about 15%w or more propylene glycol and 85%w or less water,
  • suitable pharmaceutical formulation additives preferably about 0.1 to 99%w.
  • the total concentration of the steroids in the pharmaceutical composition is 0.001 and 0.5%w, preferably 0.005 and 0.20%w, and even more preferably between about 0.01 to about 0.015%w.
  • active ingredients refers to the total amount of the mixture of at least two of compounds A through K present in the particular formulation.
  • the mixture will contain no more than 5 compounds in solution at the ratios set forth above, and even more preferably will consist of 3 of the compounds, particularly 3 chosen from compounds A,C,D,E, and F.
  • the topical, anti-inflammatory corticosteroid mixture may be prepared and applied in a cream base, i.e. a semi-solid emulsion of oil in water or water in oil.
  • a cream base i.e. a semi-solid emulsion of oil in water or water in oil.
  • an emulsion is a two phase system with one liquid (e.g. fats or oils) being dispersed as small globules in the other substance (e.g. the glycol/water solvent phase employed as the primary solvent for the corticosteroid mixture).
  • the cream formulation may contain (other than the solution of corticosteroids) fatty alcohols, surfactants, mineral oil or petrolatum and other typical pharmaceutical adjuvants such as antioxidants, antiseptics, or compatible adjuvants.
  • cream base formulation is representative of the compositions of this invention:
  • the fatty alcohol ingredient in the cream composition can be any fatty alcohol having from 16 to 24 carbons or mixtures thereof and is preferably a saturated, monohydric primary alcohol.
  • Suitable fatty alcohols include cetyl alcohol, stearyl alcohol, behenyl alcohol and the like. Vehicles having excellent properties are prepared using stearyl alcohol or mixtures of cetyl and stearyl alcohol as the fatty alcohol component.
  • the concentration of the fatty alcohol ingredients may vary between about 1 to about 20 percent by weight(%w) of the final, formulated composition.
  • the fatty alcohol will be present in amounts of about 5 to 10%w.
  • the cream formulation useful to apply the steroid combination of this invention usually will also contain an effective amount of a surfactant.
  • An effective amount is enough to assist in maintaining homogeneity of the vehicle and preventing exudation or bleeding of the more liquid components of the vehicle such as the glycol solvent upon prolonged storage at elevated temperatures.
  • the vehicle contains a quantity of the surfactant sufficient to prohibit visible exudation of the more liquid components from the vehicle after storage at 45° for 48 hours.
  • the amount of surfactant required may be small. No more of the surfactant is used than is needed to prevent this exudation. Excess quantities are undesirable because other ingredients and their functions are needlessly diluted.
  • an effective amount of surfactant will be within the range of from 0 to 10%w of the final, formulated composition, preferably about 0.1 to 5%w will be used.
  • the surfactant may be anionic, cationic, or nonionic, preferably nonionic.
  • Suitable surfactants include saturated fatty acids having from 16 to 24 carbons such as stearic acid, palmitic acid, and behenic acid; fatty amides such as oleamide, palmitamide, stearamide, and behenamide; and esters of fatty acids having from 16 to 24 carbons such as sorbitan monostearate, polyethylene glycol monostearate, propylene glycol monostearate, and the corresponding monoesters of other fatty acids such as oleic acids and palmitic acids. Best results are achieved particularly with the esters if the fatty group of the coupling agent and fatty alcohol is the same or approximately the same number of carbons. It is essential that the fatty acids be saturated and the fatty acids or amides by substantially free from irritating amounts of acids or amides having fewer than 16 carbons.
  • Span and Tween are nonionic surfactants referred to as Span and Tween.
  • the Span type materials are partial esters of common fatty acids (lauric, palmitic, stearic, and oleic) and hexitol anhydrides (hexitans and hexides), derived from sorbitol.
  • the Tween Type materials are derived from the Span products by adding polyoxyethylene chains to the nonesterified hydroxyls. Particularly valuable are Span 60, Span 80, and Tween 60 (Available through Atlas Chemical Co.).
  • a further component of a typical oil/water emulsion cream base is an effective amount of mineral oil, also referred to as mineral petrolatum, i.e. about 0 to 10%w, preferably about 1 to 8%w.
  • the cream will also include a pharmaceutically acceptable glycol solvent such as discussed above.
  • this glycol solvent will be a propylene glycol (PG)/water mixture which is 15%w PG or more, even more preferably about 30% PG but no more than 60%w PG, the mixture being present at 55-99%w, preferably 70-95%w of the total cream base formulation.
  • the glycol solvent and the fatty alcohol ingredients are the principal components in the preferred composition of the invention, the glycol solvent being the primary solvent for the corticosteroids used in the formulation although other adjuvants present such as the surfactants may also contribute significantly to the drug solubility.
  • the fluidity of the composition increases with increased concentrations of the glycol solvent, while the fatty alcohol forms a protective, lubricant and occlusive film.
  • Typical pharmaceutical adjuvants may be included as well; for example, antiseptics such as thimerosal, a pharmaceutically acceptable antioxidant such as citric acid; and other additives conventionally used to improve consistency, homogeneity, spreadability, texture, and appearance of the vehicle or it's residual film.
  • antiseptics such as thimerosal
  • a pharmaceutically acceptable antioxidant such as citric acid
  • additives conventionally used to improve consistency, homogeneity, spreadability, texture, and appearance of the vehicle or it's residual film can be used to give a residual film varying degrees of continuity, flexibility, adhesion, occlusion, water repellancy, washability and the like.
  • typical adjuvants include surfactants such as natural gums including agar, acacia gum, guar gum, tragacanth, and the like; cellulose derivatives including cellulose ethers such as methyl cellulose, ethyl cellulose, carboxymethyl cellulose, and the like; starch and starch derivatives, and water soluble vinyl polymers such as polyvinylpyrrolidone, polyvinyl alcohol, vinylpyrrolidonevinyl alcohol copolymers, and the like. Nonessential ingredients may be present at levels that vary from 0 to 5%w, but preferably less than about 1% will be present.
  • the topical, anti-inflammatory corticosteroid mixtures of this invention may also be applied as an ointment, preferably a classical ointment.
  • a "classical" ointment is a semi-solid anhydrous composition which may contain mineral oil, white petrolatum, a suitable solvent such as the glycol solvents recited hereinbefore (including propylene carbonate), and other pharmaceutically acceptable additives such as surfactants, e.g. Span, Tween, or wool fat (lanolin), stabilizers such as antioxidants (e.g. citric acid), and other adjuvants as mentioned above.
  • surfactants e.g. Span, Tween, or wool fat (lanolin
  • stabilizers such as antioxidants (e.g. citric acid), and other adjuvants as mentioned above.
  • the surfactant may be any suitable surfactant discussed hereinbefore while the solvent is preferably a compatible glycol solvent as discussed previously.
  • glycol solvent has been described hereinbefore and is preferably propylene glycol alone.
  • the composition can also contain an effective amount of a compatible plasticizer such as polyethylene glycol having a molecular weight of from above 800 to 20,000, 1,2,6-hexanetriol, sorbitol, glycerol, and the like.
  • a compatible plasticizer such as polyethylene glycol having a molecular weight of from above 800 to 20,000, 1,2,6-hexanetriol, sorbitol, glycerol, and the like.
  • the plasticizer maintains homogeneity in the fatty alcohol-glycol solvent mixture at ambient temperatures, that is, temperatures at which the fatty alcohol is naturally a solid. This component also improves the plasticity and uniformity of medicant mixtures with the vehicle and provides to the vehicle smoothness and a more pleasing "feel," hence the vehicle containing the plasticizer is more aesthetically acceptable.
  • compatible is defined herein to indicate a component which will not cause separation (loss of homogeneity) of the other components, that is, the fatty alcohol and glycol solvent at temperatures up to 45°C.
  • the plasticizer concentration can be within the range of from 0 to 15 percent. Concentrations above 15 percent may provide a composition which has a consistency unsuitable for normal applications or cause instability of the vehicle mixture and some separation of the components. In general, the particular plasticizer concentration necessary to provide a desired consistency, degree of smoothness and plasticity will vary with the choice of the fatty alcohol component, the choice of glycol solvent, and the ratio of these components in the vehicle.
  • plasticizer concentration should be balanced so the vehicle has freeze-thaw stability, i.e., does not separate after repeated cycles of solidification (by cooling) and liquefaction (by heating).
  • the vehicle of this invention can also contain a compatible, pharmaceutically acceptable coupling agent, the term compatible having the above-defined meaning.
  • Suitable coupling agents include saturated fatty acids, fatty amides, and fatty acid esters discussed hereinbefore under suitable surfactants for creams.
  • the penetrants increase the penetration and therapeutic activity of the medicants and are usually solvents or cosolvents for the medicants.
  • the penetrants can be used in concentrations which are pharmaceutically acceptable for the intended use not to exceed 20 percent of the weight of the vehicle.
  • Representative examples of penetrants include dimethylsulfoxide, dimethylacetanide, dimethylformamide, and the like.
  • medicant vehicles of this invention can also contain non-essential ingredients as discussed hereinbefore under the section entitled creams.
  • the vehicle base of U.S. Pat. No. 3,592,930 does not contain any significant quantity of petrolatum or mineral oil. It is therefore not a classical ointment and is not water-insoluble. It is preferably anhydrous, but can contain minor amounts of water such as up to 3 percent water. The water concentration should not be sufficient to cause separation of the other vehicle components or precipitant medicants dissolved in the vehicle.
  • the vehicles of this invention can be made from the above ingredients by thoroughly mixing them at ambient or elevated temperatures.
  • the active ingredients are first dissolved in the glycol solvent, the components are thoroughly mixed while each is in a liquid state, and the mixture is cooled with good agitation to room temperature. Good agitation is provided until the mixture cools to room temperature.
  • additional mechanical agitation and/or shock cooling steps can be used as intermediate or final steps in the manufacturing process to impart more homogeneity or improve texture.
  • Processing equipment suitable for these steps is known and includes heat exchangers, propeller mixers, colloid mills, homogenizers, roller mills, and the like.
  • the corticosteroid mixtures of this invention may also be applied as a lotion which is a liquid suspension or dispersion of the active ingredient in water.
  • a lotion which is a liquid suspension or dispersion of the active ingredient in water.
  • the lotion will also employ surfactants and fatty acid esters such as those set forth above in the discussion of a cream formulation, along with stabilizers such as an antioxidant and other adjuvants to improve the aesthetics of the lotion.
  • a particularly suitable glycol/water solvent mixture will be about 15 to 60%w glycol, preferably the glycol is propylene glycol present at a level of no more than 45%w of the mixture.
  • the remainder of the glycol/water mixture will be water, i.e. 40 to 85%w and preferably at least 55%w will be water.
  • a typical formulation of an acceptable lotion base which is usable in the application of the steroid mixtures of this invention is given as follows:
  • the corticosteroid mixtures of this invention may also be applied topically as a gel, that is, a solution of the drug in a colloidal gel.
  • Typical gelling agents used to prepare pharmaceutically acceptable gels include bentonite, cellulose derivatives such as methyl cellulose and carboxymethyl cellulose, tragacanth, gelatin and, preferably, carboxypolymethylene, e.g. CARBOPOL.
  • the glycol/water mixture is preferably propylene glycol/water with about 20%w glycol to about 90%w glycol, and is even more preferably at least about 60%w glycol.
  • the following is a representative formulation of the gel formulations of this invention:
  • the cream, ointment, lotion, and gel formulations discussed above may be modified to include a therapeutically effective amount of an antibiotic such s penicillin, tetracycline, oxytetracycline, neomycin, gramicidin, chlorotetracycline, erythromycin, and other antibiotics known in the art, or mixtures thereof.
  • An effective amount is whatever amount is needed to effectively reduce bacterial or fungal infections which may accompany an inflamed condition which is being treated using the corticosteroid mixture of this invention. This generally is about 0.1 to 1.0%w of the final formulation, preferably about 0.2 to about 0.5%w.
  • another aspect of this invention is an improved process of treating an inflammatory condition in animals, particularly human beings, which process comprises administering a therapeutically effective amount of an appropriate composition of this invention as described hereinbefore and those set forth in the composition claims.
  • Still another aspect of this invention comprises a process for preparing the unique compositions of this invention. This process comprises
  • An effective amount of suitable formulation additives is whatever amount is needed to form the type of formulation desired such as a cream, ointment, lotion, gel, and the like. This amount may vary from about 0.1 to about 99%w of the final formulation, while the solvent may vary from about 1%w of the formulation to about 99.9%w of the final formulation.
  • the corticosteroids will be dissolved in the solvent at elevated temperatures, e.g. 40°C to 90°C, then the formulation additives are mixed together at elevated temperatures such as 40°C to 90°C. After these individual components are prepared, they are then comixed thoroughly at elevated temperatures, again about 40°C to 90°C and cooled to ambient temperatures with constant agitation.
  • composition of this invention which is representative of the gel base formulation discussed hereinbefore.
  • the composition of this invention included compounds A,C, and D at 0.012, 0.0056 and 0.0045%w, respectively, making a total steroid concentration of 0.0221%w.
  • the penetration of the mixture was compared to the same total concentration, that is, 0.0221%w of each of the individual components.
  • the results show that at all sampling times the mixture gave a greater total drug penetration than did any of the individual components alone. The results are presented in Table 1.
  • the proportion of water in the PG/water mixture may be varied from about 85%w or more to less than 10%w, but preferably will be about 80 to about 40%w water (thus the PG/water mixture will be about 15 to 90%w PG, preferably about 20 to 60%w PG).
  • compositions VIII through XII will show a greater penetration rate than any of the corticosteroids alone in the same cream base A at an equivalent concentration.
  • Other representative cream formulations may be prepared using compounds A through K. The procedure for preparing the representative cream base composition of this invention is as follows:
  • the desired amount of the active ingredients (about 0.001 to 0.5% of the total formulated composition) is dissolved in the PG/water solution and heated to 65°-70°C.
  • the aqueous phase (1) is added to the oil phase (2) with moderate stirring and the resulting formulation cooled to 30°-35°C.
  • the desired amount of each of the corticosteroids is dissolved in the PG at about 80°-85°C.
  • the cetyl alcohol, stearyl alcohol and PEG 6000 are mixed thoroughly at 80°-85°C.
  • the PG solution (1) is added to the fatty alcohol/PEG mixture and mixed at 90°-95°C for 30 minutes, then cooled slowly to room temperature with good agitation.
  • compositions of this invention are prepared as described above:
  • compositions XIII - XIV will show a greater penetration rate than any of the corticosteroids alone in the same ointment base at an equivalent concentration.
  • Other mixtures of compounds A through K, particularly A,C,D,E, or F may similarly be prepared.
  • composition XV composition XV
  • compositions similar to composition XV may be prepared using mixtures of 2 to 5, especially 3, of the corticosteroids represented by formulas A through K, particularly those represented by formulas A,C,D,E and F. Improved penetration rates will be seen along with enhanced therapeutic response.
  • ointment based formulations may be prepared using mixtures of 2 to 5, preferably 3, compounds A through K, especially 3 member combinations of A,C,D,E, and F.
  • the formulations of Examples 1 through 5 may be modified to include a therapeutically effective amount of an antibiotic such as penicillin, tetracycline, oxytetracycline, neomycin gramicidin, chlorotetracycline, erythromycin, and other antibiotics known in the art.
  • an antibiotic such as penicillin, tetracycline, oxytetracycline, neomycin gramicidin, chlorotetracycline, erythromycin, and other antibiotics known in the art.
  • Particularly valuable in this regard are the following cream base formulations which are prepared in a manner similar to Example 4.
  • compositions similar to compositions XVII and XVIII may be prepared using mixtures of 2 to 5, especially 3, of the corticosteroids represented by formulas A through K, particularly formulas A,C,D,E, and F.

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US05/551,811 1975-02-21 1975-02-21 Pharmaceutical composition Expired - Lifetime US3934013A (en)

Priority Applications (19)

Application Number Priority Date Filing Date Title
US05/551,811 US3934013A (en) 1975-02-21 1975-02-21 Pharmaceutical composition
IL48797A IL48797A (en) 1975-02-21 1976-01-06 Topical,anti-inflammatory pharmaceutical compositions comprising at least two corticosteroids
ZA760071A ZA7671B (en) 1975-02-21 1976-01-06 Pharmaceutical composition
GB3426/76A GB1502544A (en) 1975-02-21 1976-01-28 Pharmaceutical composition
CA244,385A CA1067409A (en) 1975-02-21 1976-01-28 Anti-inflammatory composition containing corticosteroids
AU10682/76A AU504748B2 (en) 1975-02-21 1976-01-30 Corticosteroid composition
AU10858/76A AU481367B2 (en) 1975-02-21 1976-02-05 Fluidized bed treatment of kraft black with h s absorption
BR7600834A BR7600834A (pt) 1975-02-21 1976-02-10 Tratamento em leito fluidificado de licor negro kraft com absorcao de sulfeto de hidrogenio
DE19762605242 DE2605242A1 (de) 1975-02-21 1976-02-11 Entzuendungshemmendes arzneimittel zur oertlichen verwendung
FI760344A FI67415C (fi) 1975-02-21 1976-02-12 Foerfarande foer behandling av sulfatavlut
ES445151A ES445151A1 (es) 1975-02-21 1976-02-13 Un metodo de recuperar productos quimicos valiosos de la le-jia de desecho residual en un procedimiento de formacion de pasta de madera.
IT67379/76A IT1066085B (it) 1975-02-21 1976-02-18 Composizione farmaceutica antinfiammatoria a base di corticosteroidi,particolarmente per il trattamento di manifestazioni infiammatorie di dermatosi,e procedimento per la sua preparazione
NZ180042A NZ180042A (en) 1975-02-21 1976-02-18 Mixture of corticosteroids:dermatoses treatment
FR7604592A FR2301262A1 (fr) 1975-02-21 1976-02-19 Composition anti-inflammatoire
NL7601667A NL7601667A (nl) 1975-02-21 1976-02-19 Topisch, toepasbaar farmaceutisch anti-onste- kings preparaat en werkwijze voor de bereiding en toepassing ervan.
BE164436A BE838711A (fr) 1975-02-21 1976-02-19 Composition anti-inflammatoire
IE331/76A IE43655B1 (en) 1975-02-21 1976-02-19 Pharmaceutical composition
DK68876*#A DK68876A (da) 1975-02-21 1976-02-19 Betendelsesmodvirkende midler fremgangsmade til fremstilling heraf og fremgangsmade til behandling af betendelsestilstande ved anvendelse heraf
JP51017820A JPS6135166B2 (enrdf_load_stackoverflow) 1975-02-21 1976-02-20

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JP (1) JPS6135166B2 (enrdf_load_stackoverflow)
AU (1) AU504748B2 (enrdf_load_stackoverflow)
BE (1) BE838711A (enrdf_load_stackoverflow)
BR (1) BR7600834A (enrdf_load_stackoverflow)
CA (1) CA1067409A (enrdf_load_stackoverflow)
DE (1) DE2605242A1 (enrdf_load_stackoverflow)
DK (1) DK68876A (enrdf_load_stackoverflow)
ES (1) ES445151A1 (enrdf_load_stackoverflow)
FI (1) FI67415C (enrdf_load_stackoverflow)
FR (1) FR2301262A1 (enrdf_load_stackoverflow)
GB (1) GB1502544A (enrdf_load_stackoverflow)
IE (1) IE43655B1 (enrdf_load_stackoverflow)
IL (1) IL48797A (enrdf_load_stackoverflow)
IT (1) IT1066085B (enrdf_load_stackoverflow)
NL (1) NL7601667A (enrdf_load_stackoverflow)
NZ (1) NZ180042A (enrdf_load_stackoverflow)
ZA (1) ZA7671B (enrdf_load_stackoverflow)

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2624924A1 (de) 1975-05-27 1977-12-15 Syntex Inc Flunisolid und deren pharmazeutische verwendung
US4304765A (en) * 1980-10-14 1981-12-08 Alza Corporation Ocular insert housing steroid in two different therapeutic forms
EP0044543A1 (en) * 1980-07-18 1982-01-27 The Wellcome Foundation Limited Topical formulations of 9-(2-hydroxyethoxymethyl) guanine
US4432964A (en) * 1981-08-24 1984-02-21 Alza Corporation Topical composition containing steroid in two forms released independently from polymeric carrier
US4478818A (en) * 1982-12-27 1984-10-23 Alza Corporation Ocular preparation housing steroid in two different therapeutic forms
US4482539A (en) * 1983-05-13 1984-11-13 Schering Corporation Betamethasone dipropionate cream
US4489070A (en) * 1983-05-13 1984-12-18 Schering Corporation Betamethasone dipropionate cream
US4537776A (en) * 1983-06-21 1985-08-27 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl) pyrrolidone
US4552872A (en) * 1983-06-21 1985-11-12 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing corticosteroids
US4557934A (en) * 1983-06-21 1985-12-10 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one
EP0196121A1 (en) * 1985-02-22 1986-10-01 Pera Dr. Visnjic Process for obtaining the preparation for the treatment of the disease psoriasis; drug for the treatment of psoriasis and its application
EP0215622A2 (en) 1985-09-09 1987-03-25 Syntex (U.S.A.) Inc. Naphthalene anti-psoriatic agents and process for making them
US4740372A (en) * 1986-09-17 1988-04-26 Ljubomir Boncic Composition for treating psoriasis vulgaris and a method for its preparation
US4780455A (en) * 1985-04-12 1988-10-25 The Trustees Of Columbia University In The City Of New York Lipophilic complexes of pharmacologically active organic compounds
US4963555A (en) * 1980-07-18 1990-10-16 Burroughs Wellcome Co. Formulations of heterocyclic compounds
AU602871B2 (en) * 1986-02-14 1990-11-01 Pero Visnjic Procedure for obtaining the preparation for the treatment of the disease psoriasis; drug for the treatment of psoriasis and its application
US5002936A (en) * 1985-04-12 1991-03-26 Seymour Lieberman Lipophilic complexes of pharmacologically active inorganic mineral acid esters of organic compounds
US5061700A (en) * 1989-11-16 1991-10-29 Gordon Jay Dow Glyceryl acetate ointment vehicles
US5476843A (en) * 1992-10-10 1995-12-19 Roehm Pharma Gmbh Stable topical formulations with good active ingredient release characteristics, containing at least one lipophilized macrolide antibiotic
WO1996002254A1 (en) * 1994-07-15 1996-02-01 Michel Cohen SYNERGISTIC PHARMACEUTICAL COMPOSITONS CONTAINING 16'alpha',17'alpha'-ISOPROPYLIDENEDIOXY SUBSTITUTED PREGNANES
EP0727979A4 (en) * 1993-10-22 1996-11-27 Smithkline Beecham Corp NEW COMPOSITION
US5626873A (en) * 1989-03-03 1997-05-06 The Liposome Company, Inc. Emulsions
US5707981A (en) * 1994-07-28 1998-01-13 Psorial, L.L.C. Synergistic pharmaceutical compositions
US20030176408A1 (en) * 2001-12-21 2003-09-18 Gans Eugene H. Compositions and methods for enhancing corticosteroid delivery
US20060121069A1 (en) * 2000-03-31 2006-06-08 Duke University Compositions and methods for treating hair loss using oximyl and hydroxylamino prostaglandins
US20060247214A1 (en) * 2000-03-31 2006-11-02 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US7179475B1 (en) 1998-12-04 2007-02-20 Johnson & Johnson Consumer Companies, Inc. Anhydrous topical skin preparations
US20090286769A1 (en) * 2000-03-31 2009-11-19 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US20100105771A1 (en) * 2008-10-29 2010-04-29 Delong Mitchell A Amino acid salts of prostaglandins
US20100105775A1 (en) * 2008-10-29 2010-04-29 Delong Mitchell A Amino acid salts of prostaglandins
USRE43372E1 (en) 1999-03-05 2012-05-08 Duke University C16 unsaturated FP-selective prostaglandins analogs
US8618086B2 (en) 2000-03-31 2013-12-31 Duke University Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins
US8932610B2 (en) 2010-03-01 2015-01-13 Laboratorios Salvat, S.A. Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation
WO2015138650A1 (en) 2014-03-11 2015-09-17 Promius Pharma, LLC Topical corticosteroid compositions
WO2016024875A1 (en) 2014-08-11 2016-02-18 Matonis Grzegorz Cosmetic and/or pharmaceutical formulation soothing symptoms of psoriasis
US9623000B2 (en) 2008-07-31 2017-04-18 Dekel Pharmaceuticals Ltd Compositions and methods for treating inflammatory disorders
WO2019014299A1 (en) * 2017-07-11 2019-01-17 University Of Miami TOPICAL FORMULATIONS OF ACETAMINOPHENE FOR RELIEF RELIEF
US10588914B2 (en) 2009-08-31 2020-03-17 Encore Dermatology, Inc. Topical formulations comprising a steroid
US11179465B2 (en) 2014-03-11 2021-11-23 Primus Pharmaceuticals, Inc. Topical compositions comprising a corticosteroid
WO2022027041A1 (en) 2020-07-28 2022-02-03 Arcutis Biotherapeutics, Inc. Topical formulation containing jak inhibitor and laureth-4
US12161643B2 (en) 2021-12-15 2024-12-10 Arcutis Biotherapeutics, Inc. Stable formulations of SHR0302

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US4070462A (en) * 1976-10-26 1978-01-24 Schering Corporation Steroid ointment
NO774315L (no) * 1976-12-17 1978-06-20 Scherico Ltd Fremgangsmaate ved fremstilling av antibiotiske formuleringer
DE3534743A1 (de) * 1985-09-28 1987-04-02 Beiersdorf Ag Hydrocortisondiester enthaltende o/w-creme
RU2106860C1 (ru) * 1996-01-30 1998-03-20 Акционерное общество открытого типа "Нижегородский химико-фармацевтический завод" Состав и способ получения мази противовоспалительного и противозудного действия

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US3073743A (en) * 1959-07-30 1963-01-15 Upjohn Co Antiinflammatory steroid acetonide compositions and therapy
US3472931A (en) * 1969-01-17 1969-10-14 Foster Milburn Co Percutaneous absorption with lower alkyl amides

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US3073743A (en) * 1959-07-30 1963-01-15 Upjohn Co Antiinflammatory steroid acetonide compositions and therapy
US3472931A (en) * 1969-01-17 1969-10-14 Foster Milburn Co Percutaneous absorption with lower alkyl amides

Cited By (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2624924A1 (de) 1975-05-27 1977-12-15 Syntex Inc Flunisolid und deren pharmazeutische verwendung
DE2661037C2 (enrdf_load_stackoverflow) * 1975-05-27 1989-04-06 Syntex (U.S.A.) Inc., Palo Alto, Calif., Us
EP0044543A1 (en) * 1980-07-18 1982-01-27 The Wellcome Foundation Limited Topical formulations of 9-(2-hydroxyethoxymethyl) guanine
US4963555A (en) * 1980-07-18 1990-10-16 Burroughs Wellcome Co. Formulations of heterocyclic compounds
US4304765A (en) * 1980-10-14 1981-12-08 Alza Corporation Ocular insert housing steroid in two different therapeutic forms
US4432964A (en) * 1981-08-24 1984-02-21 Alza Corporation Topical composition containing steroid in two forms released independently from polymeric carrier
US4478818A (en) * 1982-12-27 1984-10-23 Alza Corporation Ocular preparation housing steroid in two different therapeutic forms
US4489070A (en) * 1983-05-13 1984-12-18 Schering Corporation Betamethasone dipropionate cream
US4482539A (en) * 1983-05-13 1984-11-13 Schering Corporation Betamethasone dipropionate cream
US4552872A (en) * 1983-06-21 1985-11-12 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing corticosteroids
US4557934A (en) * 1983-06-21 1985-12-10 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one
US4537776A (en) * 1983-06-21 1985-08-27 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl) pyrrolidone
EP0129283A3 (en) * 1983-06-21 1987-11-11 The Procter & Gamble Company Improved penetrating topical pharmaceutical compositions containing corticosteroids
EP0196121A1 (en) * 1985-02-22 1986-10-01 Pera Dr. Visnjic Process for obtaining the preparation for the treatment of the disease psoriasis; drug for the treatment of psoriasis and its application
US4780455A (en) * 1985-04-12 1988-10-25 The Trustees Of Columbia University In The City Of New York Lipophilic complexes of pharmacologically active organic compounds
US5002936A (en) * 1985-04-12 1991-03-26 Seymour Lieberman Lipophilic complexes of pharmacologically active inorganic mineral acid esters of organic compounds
EP0215622A2 (en) 1985-09-09 1987-03-25 Syntex (U.S.A.) Inc. Naphthalene anti-psoriatic agents and process for making them
AU602871B2 (en) * 1986-02-14 1990-11-01 Pero Visnjic Procedure for obtaining the preparation for the treatment of the disease psoriasis; drug for the treatment of psoriasis and its application
US5004736A (en) * 1986-02-14 1991-04-02 Pero Visnjic Procedure for obtaining the preparation for the treatment of the disease psoriasis: drug for the treatment of psoriasis and its application
US4740372A (en) * 1986-09-17 1988-04-26 Ljubomir Boncic Composition for treating psoriasis vulgaris and a method for its preparation
US5626873A (en) * 1989-03-03 1997-05-06 The Liposome Company, Inc. Emulsions
US5061700A (en) * 1989-11-16 1991-10-29 Gordon Jay Dow Glyceryl acetate ointment vehicles
US5476843A (en) * 1992-10-10 1995-12-19 Roehm Pharma Gmbh Stable topical formulations with good active ingredient release characteristics, containing at least one lipophilized macrolide antibiotic
US5559098A (en) * 1992-10-10 1996-09-24 Roehm Pharma Gmbh Stable topical formulations with good active ingredient release characteristics, containing at least one lipophilized macrolide antibiotic
EP0727979A4 (en) * 1993-10-22 1996-11-27 Smithkline Beecham Corp NEW COMPOSITION
WO1996002254A1 (en) * 1994-07-15 1996-02-01 Michel Cohen SYNERGISTIC PHARMACEUTICAL COMPOSITONS CONTAINING 16'alpha',17'alpha'-ISOPROPYLIDENEDIOXY SUBSTITUTED PREGNANES
US5707981A (en) * 1994-07-28 1998-01-13 Psorial, L.L.C. Synergistic pharmaceutical compositions
USRE36606E (en) * 1994-07-28 2000-03-07 Massa Technology S.A. Synergistic pharmaceutical compositions
US7179475B1 (en) 1998-12-04 2007-02-20 Johnson & Johnson Consumer Companies, Inc. Anhydrous topical skin preparations
USRE43372E1 (en) 1999-03-05 2012-05-08 Duke University C16 unsaturated FP-selective prostaglandins analogs
US8618086B2 (en) 2000-03-31 2013-12-31 Duke University Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins
US9346837B2 (en) 2000-03-31 2016-05-24 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US9675539B2 (en) 2000-03-31 2017-06-13 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US20060121069A1 (en) * 2000-03-31 2006-06-08 Duke University Compositions and methods for treating hair loss using oximyl and hydroxylamino prostaglandins
US20060247214A1 (en) * 2000-03-31 2006-11-02 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US9579270B2 (en) 2000-03-31 2017-02-28 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US8906962B2 (en) 2000-03-31 2014-12-09 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US8541466B2 (en) 2000-03-31 2013-09-24 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US20090286769A1 (en) * 2000-03-31 2009-11-19 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US20100210615A2 (en) * 2001-12-21 2010-08-19 Eugene Gans Compositions and methods for enhancing corticosteroid delivery
EP2363150A1 (en) * 2001-12-21 2011-09-07 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US20070142343A1 (en) * 2001-12-21 2007-06-21 Gans Eugene H Compositions and methods for enhancing corticosteroid delivery
US20040198709A1 (en) * 2001-12-21 2004-10-07 Gans Eugene H. Compositions and methods for enhancing corticosteroid delivery
US20070142344A1 (en) * 2001-12-21 2007-06-21 Gans Eugene H Compositions and methods for enhancing corticosteroid delivery
US7771733B2 (en) 2001-12-21 2010-08-10 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US20100210614A2 (en) * 2001-12-21 2010-08-19 Eugene Gans Compositions and methods for enhancing corticosteroid delivery
US20100210609A2 (en) * 2001-12-21 2010-08-19 Eugene Gans Compositions and methods for enhancing corticosteroid delivery
US20090176750A1 (en) * 2001-12-21 2009-07-09 Gans Eugene H Compositions and methods for enhancing corticosteroid delivery
US7217422B2 (en) * 2001-12-21 2007-05-15 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US7794738B2 (en) 2001-12-21 2010-09-14 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US20030186951A1 (en) * 2001-12-21 2003-10-02 Gans Eugene H. Compositions and methods for enhancing corticosteroid delivery
US8232264B2 (en) 2001-12-21 2012-07-31 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US20120289490A1 (en) * 2001-12-21 2012-11-15 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US7220424B2 (en) * 2001-12-21 2007-05-22 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US20030176408A1 (en) * 2001-12-21 2003-09-18 Gans Eugene H. Compositions and methods for enhancing corticosteroid delivery
WO2003055445A3 (en) * 2001-12-21 2003-10-09 Medicis Pharmaceutical Corp Compositions and methods for enhancing corticosteriod delivery
US6765001B2 (en) * 2001-12-21 2004-07-20 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US9623000B2 (en) 2008-07-31 2017-04-18 Dekel Pharmaceuticals Ltd Compositions and methods for treating inflammatory disorders
US20100105771A1 (en) * 2008-10-29 2010-04-29 Delong Mitchell A Amino acid salts of prostaglandins
US8722739B2 (en) 2008-10-29 2014-05-13 Novaer Holdings, Inc. Amino acid salts of prostaglandins
US8623918B2 (en) 2008-10-29 2014-01-07 Novaer Holdings, Inc. Amino acid salts of prostaglandins
US20100105775A1 (en) * 2008-10-29 2010-04-29 Delong Mitchell A Amino acid salts of prostaglandins
US10588914B2 (en) 2009-08-31 2020-03-17 Encore Dermatology, Inc. Topical formulations comprising a steroid
US10905697B2 (en) 2009-08-31 2021-02-02 Encore Dermatology, Inc. Topical formulations comprising a steroid
US8932610B2 (en) 2010-03-01 2015-01-13 Laboratorios Salvat, S.A. Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation
US11179465B2 (en) 2014-03-11 2021-11-23 Primus Pharmaceuticals, Inc. Topical compositions comprising a corticosteroid
WO2015138650A1 (en) 2014-03-11 2015-09-17 Promius Pharma, LLC Topical corticosteroid compositions
WO2016024875A1 (en) 2014-08-11 2016-02-18 Matonis Grzegorz Cosmetic and/or pharmaceutical formulation soothing symptoms of psoriasis
WO2019014299A1 (en) * 2017-07-11 2019-01-17 University Of Miami TOPICAL FORMULATIONS OF ACETAMINOPHENE FOR RELIEF RELIEF
WO2022027041A1 (en) 2020-07-28 2022-02-03 Arcutis Biotherapeutics, Inc. Topical formulation containing jak inhibitor and laureth-4
US11730740B2 (en) 2020-07-28 2023-08-22 Arcutis Biotherapeutics, Inc. Laureth-4 containing topical formulations
US12083122B2 (en) 2020-07-28 2024-09-10 Arcutis Biotherapeutics, Inc. Laureth-4 containing topical formulations
US12161643B2 (en) 2021-12-15 2024-12-10 Arcutis Biotherapeutics, Inc. Stable formulations of SHR0302

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Publication number Publication date
FR2301262A1 (fr) 1976-09-17
BR7600834A (pt) 1976-09-14
JPS51110043A (enrdf_load_stackoverflow) 1976-09-29
FI67415C (fi) 1985-03-11
IE43655B1 (en) 1981-04-22
IT1066085B (it) 1985-03-04
CA1067409A (en) 1979-12-04
FI67415B (fi) 1984-11-30
ZA7671B (en) 1977-08-31
IE43655L (en) 1976-08-21
IL48797A (en) 1979-01-31
ES445151A1 (es) 1977-05-16
DK68876A (da) 1976-08-22
FR2301262B1 (enrdf_load_stackoverflow) 1979-04-06
NL7601667A (nl) 1976-08-24
AU1068276A (en) 1977-08-04
AU1085876A (en) 1977-03-17
GB1502544A (en) 1978-03-01
NZ180042A (en) 1978-07-28
DE2605242A1 (de) 1976-09-02
BE838711A (fr) 1976-08-19
FI760344A7 (enrdf_load_stackoverflow) 1976-08-22
AU504748B2 (en) 1979-10-25
JPS6135166B2 (enrdf_load_stackoverflow) 1986-08-12
IL48797A0 (en) 1976-03-31

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